Is ACE p.Ser5fs (c.12_31del) pathogenic?

ACE p.Ser5fs (c.1231del) is classified Pathogenic/Likely pathogenic in ACE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-02-28). Ultra-rare (popmax 0.0288%, mid); Associated with renal tubular dysgenesis.

What condition is associated with ACE p.Ser5fs (c.12_31del)?

ACE p.Ser5fs (c.12_31del) is associated with renal tubular dysgenesis (ClinVar).

How common is ACE p.Ser5fs (c.12_31del) in the general population?

ACE p.Ser5fs (c.12_31del) is ultra-rare (popmax 0.0288%, mid) (gnomAD).

ACE p.Ser5fs

c.12_31del · rs797045079 · VCV208559

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0288%, mid)

Conditions

renal tubular dysgenesis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 25
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.2	GERP 0.72, phastCons 0.14
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	(GCTGCC)n simple repeat · ambiguous alignment · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0288% Middle Eastern · 1/3,472 alleles

Filtering AF 7.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.1e-05%

Overall 0.000304% 4/1,317,378 alleles · ultra-rare exomes 1/1,165,988 · genomes 3/151,390 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0288%	3,472
European (non-Finnish)	0.000288%	347,039

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ACE
Protein: p.Ser5fs
Coding: c.12_31del
MANE Select: NM_000789
dbSNP: rs797045079
Type: Deletion
Location: chr17:63477106 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.38 · 97 PDB

Full ACE gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

renal tubular dysgenesis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACE p.Leu454fs Pathogenic ★ same condition
ACE p.Phe300fs Pathogenic ★ same condition
ACE p.Leu16_Pro23del Conflicting classifications of pathogenicity ★ same condition
ACE p.Ser5Leu Uncertain significance ★ ⚠ same residue
ACE p.Ser5= Likely benign ★ same residue
ACE p.Leu440fs Pathogenic same condition
ACE c.1709+5G>C Pathogenic/Likely pathogenic ★★ same condition
ACE c.3503+1G>C Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ace-p-ser5fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown